Current head and neck (H&N) intensity modulated radiotherapy (IMRT) techniques cause severe discomfort and functional morbidity. One explanation is that IMRT cannot compensate for changes in the location and shape of disease and normal anatomy during treatment, leading to exposure of normal mucosa and salivary gland to higher than anticipated doses. Adaptive radiotherapy (ART) is a novel approach to correct for such variations throughout a six to seven-week treatment course via automated target re-localization and treatment modification. Our in-house ART approach is fully operational and pushes beyond all prior preclinical work via the use of daily in-room CT imaging and automated deformable image registration tools. Reduced treatment of bystander tissues with H&N ART would provide an opportunity for complementary dose escalation in patients with refractory tumor. However, proven localization of resistant disease early during treatment remains elusive. Advanced MR imaging (MRI) techniques promise to fill this void. Diffusion-weighted MRI (DW-MRI) and dynamic contrast enhanced MRI (DCE-MRI) are novel but increasingly proven modalities which can provide critical prognostic biological information, such as early fluctuations in tumor cellular density and perfusion, signifying disease response or resistance with sub-millimeter resolution. DW-MRI parameters have been shown to predict outcome of brain tumors following radiation therapy, but such experience with MRI in head and neck cancer remains sparse. This proposed trial will be the first to prospectively investigate the clinical impact of ART in H&N cancer patients and to establish proof-of-principle that MRI complements the advantages of ART. We hypothesize that ART guided by daily in-room CT will accurately define and compensate for tumor and normal anatomy changes during treatment and that serial MRI will predict treatment outcomes and feasibly guide dose escalation to high-risk disease. As a result, this approach will significantly improve both normal tissue toxicity and tumor targeting while maintaining real-world treatment efficiency. This project will permit collection of preliminary data for confirmatory phase II and III clinical trials. Aims: 1a) To demonstrate improved normal tissue sparing dosimetry with H&N ART planning relative to standard IMRT planning based on a single simulation CT. 1b) To confirm improved acute toxicity outcomes in oropharyngeal cancer patients treated with ART. 2) To provide proof-of-principle that serial DCE-MRI and DW-MRI can predict disease response and guide dose-escalated ART to refractory tumor. Methods: We will enroll 30 patients with newly diagnosed stage III-IVb oropharyngeal cancer. We will treat all patients with ART, and perform serial DCE-MRI and DW-MRI at baseline, mid-treatment, and post-treatment. We will evaluate patients with MDASI-HN toxicity surveys, sialometry, swallowing outcomes, and dietary evaluations at regular intervals and compare to matched oropharyngeal IMRT case controls previously treated in our clinic. For Specific Aim #1a, we will perform paired normal tissue and tumor dosimetric analysis of ART and standard IMRT plans for each subject. For Specific Aim #1b, we will perform paired analysis of resting/stimulated salivary flow volumes, MDASI-HN scores, weight, and dietary tolerance between ART study subjects and case controls at baseline, treatment completion, and longitudinally after treatment. For Specific Aim #2, we will correlate serial DCE-MRI and DW-MRI with disease response outcomes. We will subsequently design hypothetical ART dose escalation plans. In these plans, we will contour refractory primary or nodal GTV (GTV-R) identified by serial DW-MRI obtained mid-treatment, and boost this GTV-R to 85 Gy or until dose constraints are reached. We will catalog the amount of dose escalation and degree of normal tissue dose sparing preserved for each subject. PUBLIC HEALTH RELEVANCE: Head and neck radiotherapy causes severe complications and frequently cannot control disease. The goal of this pilot clinical trial is to test whether radiation treatment which actively adapts to changes in a patient's tumor and normal tissues during a six-week course of treatment can reduce or prevent toxicity. This trial is also designed to provide proof-of-principle that advanced MRI imaging techniques can quickly identify patients with high-risk disease and guide additional treatment towards refractory regions of tumor while the patient is still receiving therapy.